The long-term objective of this proposal is to understand how cell surface receptors and ion channels detect extracellular signals and transduce this information into physiological changes at the cellular and organismal level. This project will focus on a novel receptor that is activated by capsaicin, the main pungent ingredient in 'hot' chili peppers. Capsaicin and other vanilloid compounds elicit a sensation of burning pain by activating non- selective cation channels on primary sensory nerve endings. Capsaicin receptors are also activated by acid and noxious heat, making them potentially important components of the pain transduction pathway in vivo A combination of molecular genetic, biochemical, and electrophysiological techniques will be used to probe the mechanisms whereby capsaicin receptors detect and respond to chemical and physical stimuli. The specific aims of the proposal are to: (i) isolate and characterize novel capsaicin receptor- related receptors from the mammalian nervous system; (ii) pinpoint domains of the capsaicin receptor that detect vanilloid compounds, protons, or heat; (iii) determine whether and how cytoplasmic second messenger signaling systems contribute to receptor desensitization or potentiation by inflammatory agents; (iv) identifying cellular proteins that interact with the capsaicin-gated channel to regulate desensitization, synaptic localization, or subunit assembly. The capsaicin receptor may play an important role in peripheral nervous system pathways that contribute to acute and chronic pain. The proposed studies will help to clarify the molecular mechanisms underlying these processes and facilitate the development of novel analgesic agents for treating peripheral pain syndromes, such as those associated with rheumatoid arthritis, viral and diabetic neuropathies, or peri-operative wound healing.